In recent years, the development of diseases of the circulatory system in the middle-aged and elderly groups, which are called adult diseases, has increased due to a change in dietary lifestyle and an increase in intrinsic and extrinsic stress, and this increase has become a serious problem. According to statistics provided by the Korean National Statistical Office in 2008, cerebrovascular diseases and heart diseases, including atherosclerosis, cerebral hemorrhage, stroke and cerebral infarction, are the first or second leading cause of death among death causes except for cancer. The major cause of these diseases is thrombus, and thrombosis is a pathology caused by excessive platelet aggregation. When blood vessels are damaged, platelets are activated by agonists such as collagen, thrombin, ADP (adenosine diphosphate) and the like, resulting in platelet adhesion, secretion and aggregation. This process plays an important role not only in hemostasis, but also in the development of diseases of the circulatory system, including thrombosis.
Coronary artery disease, a disease of the circulatory system, is known as one of causes of death, which are most frequent worldwide. Particularly, acute coronary syndrome is a coronary artery disease that is the direct cause of death. Acute coronary syndrome can be divided into unstable angina, non-ST-segment elevation myocardial infarction (NSTE; non Q-wave MI), and ST-elevation myocardial infarction (STE MI; Q-wave MI), and the former two also are collectively referred to as NSTE ACS (non-ST-elevation acute coronary syndrome), because treatment and prognosis are similar between the two. In chronic stable angina, ischemia is caused by a decrease in the effective diameter of coronary arteries due to atherosclerosis, but acute coronary syndrome has a mechanism different from that of chronic stable angina. Acute coronary syndrome occurs when blood flow is rapidly reduced or blocked by intracoronary acute thrombosis caused by the rupture or erosion of an atherosclerotic plaque.
More specifically, in acute coronary syndrome, the intravascular thrombotic process is the same as the process in which hemostasis occurs after traumatic vascular injury. In other words, when the rupture or erosion of a vulnerable atherosclerotic plaque occurs, connective tissue below endothelial cells is exposed to blood. Platelets in blood adhere to the exposed connective tissue (platelet adhesion), and the platelets are activated by mechanical and biochemical stimulation to secrete TxA2 (thromboxane A2), ADP (adenosine diphosphate), epinephrine and the like (platelet activation). These secreted substances activate GP IIb/IIIa receptor on the platelet surface, and the activated GP IIb/IIIa receptor causes platelets to aggregate by fibrinogen (platelet aggregation). Platelets are activated by many pathways, but are finally aggregated by fibrinogen through GP IIb/IIIa receptor, and thus this process is the final common pathway of platelet aggregation. Primarily produced thrombus is “white thrombus” rich in platelets and corresponds to the primary hemostasis of a hemostasis process.
The produced PRT (platelet-rich thrombus) is produced on the vascular wall of the injury portion of atherosclerotic plaques and usually does not completely occlude coronary arteries (Mural thrombus). This clinically corresponds to NTSE ACS. On PRT (platelet-rich thrombus), thrombin (factor IIa) is produced by activation of coagulation and chain reactions. Thrombin activates fibrinogen to fibrin, and activated fibrin forms a meshwork while a thrombus containing blood cells such as red blood cells is formed. The formed thrombus is “red thrombus” and corresponds to the secondary hemostasis of the hemostasis process. Thrombosis/thrombolysis balance is continued toward thrombolysis production, blood vessels are completely occluded, resulting in STE MI.
Antithrombotic drugs can be divided into anti-platelet agents for inhibiting platelets which are involved in primary hemostasis, and anticoagulants for inhibiting coagulation in secondary hemostasis. Anti-platelet agents include aspirin which inhibits TxA2 production, clopidogrel and ticlopidine, which are ADP receptor blockers, abciximab that is a GP IIb/IIIa receptor blocker, and the like. In addition, theopylline, molsidomine, verapamil, nifedipine, nitroglycerine and the like are known to promote of cAMP and cGMP, which inhibit the recruitment of Ca2+. Anticoagulants include heparin that activates antithrombin III to degrade thrombin, the direct thrombin inhibitor (DTI) hirudin, the vitamin K antagonist warfarin and so on. However, the above-mentioned drugs can cause various side effects, including excessive inhibition of hemostasis in the human body, sterility, and disorders of the digestive system. Thus, there is a need to develop an agent, which significantly reduces the side effects of antithrombotic drugs and, at the same time, is safe.